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Paediatrica Indonesiana, Vol. 43 No. 3-4 March - April 2003 59

Paediatrica IndonesianaVOLUME 43 NUMBER 3-4March - April 2003

Original Article

From the Department of Child Health, Medical School, University ofUdayana, Sanglah Hospital, Denpasar.

Reprint requests to: Ida Bagus subanada, MD, Department of ChildHelath, Medical School, Udayana University, Denpasar, Indonesia. Tel.62-361-27911, Fax. 62-361-224 206.

The incidence of hyperbilirubinemia in

premature infants is still high. Monintja(quoted from Ismail1) reported that its

incidence was 43%. The complication ofhyperbilirubinemia is bilirubin encephalopathy or

kernicterus attributable to the neurotoxicity of

unconjugated bilirubin. Toxic effect of unconjugated

bilirubin occurs when unbound unconjugated bilirubinpasses through the blood brain barrier (BBB), binds

to phospholipid and ganglioside of neuronal plasma

membrane and finally causes neuronal death.2-5 In

premature infants, bilirubin encephalopathy candevelop without marked hyperbilirubinemia.6Some

investigators reported various incidence of bilirubin

encephalopathy. Ahdab-Barmadaet al(quoted fromVolpe5, Connolly7, Menkes8) reported the incidence

of bilirubin encephalopathy in premature infants was

25%. Wolf et al9demonstrated that 22% of neonates

with hyperbilirubinemia develop bilirubin

encephalopathy. Wilson-Castello 10in a case controlstudy reported that 33.3% of children with

neurological impairment had a history of

hyperbilirubinemia in the neonatal period. On the

other hand, the neurological impairment of premature

infants without hyperbilirubinemia was 6-9%.11

Neurological impairment of children with history of

prematurity and neonatal hyperbilirubinemia

Ida Bagus Subanada, MD; I Komang Kari, MD; Abdul Hamid, MD

ABSTRACT

Background In premature infants, the incidence of hyperbiliru-binemia is still high. Bilirubin encephalopathy can develop withoutmarked hyperbilirubinemia.

ObjectiveTo know the incidence of neurological impairment inpremature with hyperbilirubinemia and the association betweenneurological impairment and serum unconjugated billirubin con-centration.

Methods

A retrospective study was conducted on 54 prematures

with history of hyperbilirubinemia and 54 without history of hyper-bilirubinemia born between 1997 and 1998 and discharged fromSanglah Hospital. Consecutive sampling was done. After univariateanalysis, multivariate analysis was used to identify the associationbetween serum unconjugated bilirubin concentration and neuro-

logical impairment at the adjusted age of 18 months.

Results There were statistically significant differences in mean of

age and neurological impairment between subjects with and with-out hyperbilirubinemia (p

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Paediatrica Indonesiana

60 Paediatrica Indonesiana, Vol. 43 No. 3-4 March - April 2003

Concomitant with the increase of the quality of

neonatal care, life expectancy of premature infantswith hyperbilirubinemia is also increased. On the other

hand, disability that emerges can produce serious prob-

lems for their family. Motivated by the known neuro-toxicity of unconjugated bilirubin and serious prob-

lems that occurred, we conducted a study to knowthe incidence of neurological impairment and their

association with serum unconjugated bilirubin con-

centration in the neonatal period.

Methods

The samples were derived from medical record of

Neonatology Division at Sanglah Hospital Denpasar

who were born between January 1997 and January

1998. Consecutive sampling was done to get 108subjects. All subjects had 18 months of corrected

age and prematurity history with 30-37 week

gestational age The sample consisted of 54 childrenwith history of hyperbilirubinemia and 54 children

without history of hyperbilirubinemia in the neonatal

period. Gender was matched, but gestational age, birth

weight, and age were compared in both groups.Confounding variables such as toxemia gravidarum,

abdomen X-ray during pregnancy, fetal distress,

asphyxia, respiratory distress syndrome, hypoglycemia

(blood sugar 15 minutes,operative delivery, partus praesipitatus, intracranial

bleeding, head injury, malnourished, microcephaly,

macrocephaly, and heart failure were excluded. Homevisit was done for all cases that were eligible for this

study. Confounding variables were also derived byquestionnaire at the time of home visit. In the

hyperbilirubinemic group, serum unconjugated

bilirubin concentration, gestational age, birth weight,serum albumin concentrations, gender, and age

between subjects who had neurological impairment

and who had no neurological impairment were

compared. Hyperbilirubinemia was defined as serumunconjugated bilirubin concentration >10 mg/dL.

Gestational age was defined based on Dubowitz score.

Neurological impairment was defined as one or more

of the following: cerebral palsy, hearing loss, andstrabismus. Cerebral palsy was established if we found

4 of 6 Levines criteria, and there were no evidence of

progressive neurological impairment. Hearing loss was

defined as the absence of response to paper frictionrub to both side ears.

Chi-square test was used to compare categorical

variables, and two-tailed ttest to compare continuous

variables. Variables with p

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Ida Bagus Subanada et al:Neurological impairment and neonatal hyperbilirubinemia


nificant differences in the means of serum

unconjugated bilirubin concentration, gestationalage, birth weight, and serum albumin concentra-

tion between subjects who had neurological im-

pairment and subjects who had no neurologicalimpairment, but the mean age and gender were

not statistically significant.Multivariate analysis showed that neurological

impairment was significantly associated with serum

unconjugated bilirubin concentration, gestationalage, and serum albumin concentration; but not with

birth weight. About 56.1% of the neurological im-

pairment was associated with serum unconjugated

bilirubin concentration, gestational age, serum al-bumin concentration, and birth weight.

Discussion

Kernicterus is the term used to describe yellow staining

of the basal ganglia and nuclear areas of the brain in

newborn infants dying with severe jaundice. Bilirubinencephalopathy is also used (interchangeably with

Results

From July 2000 to July 2001, there were 136 cases

who visited our hospital. Twenty eight subjects were

lost to follow up, 25 because their addresses were notfound, 2 children died, and one refused to join. There

were statistically significant differences in neurologicalimpairment between the subjects with and without

history of neonatal hyperbilirubinemia (Table 1).

The relative risk was 4.5 (95%CI 1.02;19.87). Ofnine subjects who had neurological impairment in

the hyperbilirubinemic group, 8 had cerebral palsy,

3 had hearing loss, and 3 had strabismus. All subjects

who had hearing loss and 2 subjects who hadstrabismus also had cerebral palsy. Both subjects with

neurological impairment in non-hyperbilirubinemic

group had cerebral palsy.

Table 2

shows the characteristics of subjects inboth groups. There was a statistically significant differ-

ence in the mean of age between both groups, but no

significant difference in gestational age and birth weight.

In subjects with history of neonatal hyperbi-lirubinemia (Table 3), there were statistically sig-

TABLE3. CHARACTERISTICSOFSUBJECTWITHNEONATALHYPERBILIRUBINEMIAHISTORYWHOHADANDWHODIDNOTHAVENEUROLOGICAL IMPAIRMENT

Characteristics Neonatal hyperbilirubinemia

Neurological Neurological t p 95%CIimpairment (+) impairment (-)

Mean UB (mg/dL)* 16.8 (SD2.4) 14.4 (SD 2.3) 2.94 0.005 0.78;4.41Mean GA (mo)* 32.0 (SD 1.1) 34.0 (SD 2.0) -4.14 0.001 -2.97;-0.98Mean BW (g)* 1821.1 (SD 144.5) 2036.0 (SD 264.3) -3.57 0.002 -350.90;-92.21Mean Alb (g/dL)* 2.7 (SD 0.2) 3.1 (SD 0.3) -5.09 0.000 -0.62;-0.27Mean age (mo)* 48.2 (SD 2.4) 46.8 (SD 3.1) 1.28 0.208 -0.80;3.60Male (%)** 5 (55) 23 (51.1) 0.06 0.808

Abbreviation : UB :Unconjugated bilirubin GA :Gestational of ageBW :Body weight Alb :Albumin* :Analyzed by two-tailed ttest ** :Analyzed by Chi-square test

TABLE4. MULTIVARIATEANALYSISOFASSOCIATIONBETWEENCHARACTERISTICSOFSUBJECTSANDNEUROLOGICAL IMPAIRMENT

Characteristics R2 p

UB (mg/dL) 0.561

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kernicterus) to describe an acute or chronic neurological

syndrome that is believed to reflect bilirubin toxicity.2

Three conditions occurred when the brain is

exposed to unconjugated bilirubin i.e., [1] without

functional disturbances and clinical manifestations,[2] with reversible functional disturbance, and [3]

disruption of structure and function of the brain. Inpremature infants, the third condition is the most

common manifestation.

The clinical features of infants who have sus-tained bilirubin injury to their brain in the neonatal

period depend upon the topography of the neuro-

pathological findings and their interrelations with

brain maturation. Because of these interrelations, theclinical features differ according to the age of the in-

fants. 5,8One study of the occurrence and nature of

the clinical features of infants with marked hyperbi-

lirubinemia who have either died with pathologicallyproven kernicterus or survived to develop the clinical

syndrome of chronic bilirubin encephalopathy of the

post kernicterus, reported that about 55-65% of cases

with definite neurological signs, 20-30% with equivo-cal neurological signs, and 15% without definite neu-

rological signs. 5In our study, the incidence of neuro-

logical impairment in children with premature and

neonatal hyperbilirubinemia was 17%. From the medi-cal record we found that none of them showed acute

clinical manifestations. This was associated with im-

maturity of the brain attributable to premature infants.

Wolf et al9demonstrated that 22% of children withhistory of neonatal hyperbilirubinemia had neurologi-

cal impairment. Ahdab-barmada et al (quoted from

Connolly7) found the neurological impairment in chil-

dren born premature with history of neonatal hyper-bilirubinemia was 25%. In a case-control study, Wil-

son-Castello et al10 reported that 33.3% of children

with neurological impairment had history of neonatalhyperbilirubinemia. The different result of these stud-

ies may be due to the difference in cut off point of

bilirubin concentration (10 mg/dL in our study and

23.4 mg/dL in Wolfs study), gestational age (25-34weeks in Ahdab-Barmadas study and 30-37 weeks inour study), and the design of study (cohort retrospec-

tive in our study and case control in Wilson-Castellos

study).

Neurological impairment occurs in premature orlow birth weight infants due to immaturity of struc-

ture and function of organ especially the brain.11-13

On the other hand, clinical features of neurological

impairment in children with history of neonatal hy-perbilirubinemia are delayed in some cases. Clinical

features become clearer in older than younger chil-

dren. 7,14The incidence of bilirubin encephalopathyis greater in male than female infants. 15,16In our study,

there were no statistically significant differences in themeans of gestational age, birth weight and gender

between subjects with and without history of neona-

tal hyperbilirubinemia. Although the mean age dif-fered between the two groups (Table 2), the incidence

of neurological impairment was not influenced. This

was because the difference was not so large ( 3.7

months).There are some important determinants of neu-

ronal injury caused by bilirubin, including:5,17[1] con-

centration of serum-unconjugated bilirubin, [2] con-

centration of serum albumin, [3] bilirubin binding byalbumin, [4] concentration of hydrogen ions-acido-

sis, [5] blood-brain barrier (BBB), and [6] neuron

susceptibility. In premature or low birth weight infants,

the permeability of BBB is increased due to immatu-rity. This is why the incidence of bilirubin encephal-

opathy was greater in the premature and low birth

weight infants than that in full term infants.5,17

The correlation between neurotoxicity and eleva-tion of serum-unconjugated bilirubin is not so great.

Concentration of serum albumin is more important in

determining the neurotoxicity of unconjugated biliru-

bin. At lower concentration of serum albumin, the over-all reaction will favor formation of unbound bilirubin

anion and ultimately bilirubin acid. Bilirubin acid is the

toxic form of unconjugated bilirubin.5 In the patho-

genesis of bilirubin encephalopathy, the increased per-meability of BBB is also important. In premature or low

birth weight infants, the BBB is more permeable than

full term infants.6

Usually the neurotoxicity effect of unconjugated

bilirubin occurs when its level is more than 20 mg/

dL.3,6,18-24 In premature infants, bilirubin encephal-

opathy can develop without marked hyperbilirubine-mia. This is due to incomplete formation of BBB andlow serum albumin concentration.6 There were nega-

tive correlation between the gestational age and the

elevation of serum bilirubin concentration,25-27 per-

meability of BBB;6and positive correlation betweenthe gestational age and serum albumin concentra-

tion.28In our study, the mean of serum unconjugated

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bilirubin concentration was greater, but the mean ges-

tational age and serum albumin concentration waslower in subjects with neurological impairment than

subjects without neurological impairment. This con-

dition results in elevation of serum unbound bilirubinconcentration and is accompanied by increased per-

meability of BBB, ultimately the probability of biliru-bin encephalopathy was also increased. This result was

confirmed by multivariate analysis and found that

there were relationships between neurological impair-ment and the mean of serum unconjugated bilirubin

concentration, serum albumin concentration, and

gestational age. A collaborative perinatal case-con-

trol study29reported that 57 out of 61 (93.4%) chil-dren who had neurological impairment at 7 years of

age had history of serum unconjugated bilirubin con-

centration of less than 10 mg/dL. This finding indi-

cated that bilirubin encephalopathy has developedwithout marked hyperbilirubinemia. Delayed motor

development in the first year was demonstrated in

premature infants with moderate hyperbilirubinemia

in the Collaborative Perinatal Project,30and a largeprospective study of premature infants with follow up

through age 2 years demonstrated a dose-response re-

lationship between maximal neonatal bilirubin level

and risk for impaired neurodevelopment outcome at2 years.31Wolf et al9found 22% of neonates with hy-

perbilirubinemia develop bilirubin encephalopathy.

Wilson-Castello et al10in a case-control study reported

that 33.3% of children with neurological impairmenthad history of neonatal hyperbilirubinemia. On the

other hand, a retrospective cohort study by OShea et

al32in one year old (corrected age) children with very

low birth weight history demonstrated that there wasno relationship between hyperbilirubinemia and neu-

rological impairment. This study was supported by Yeo

et al14in a retrospective cohort study in neonates withhyperbilirubinemia who underwent phototherapy.

They found that there was no relationship between

hyperbilirubinemia and neurological impairment. The

different results of these studies may be due to thedifference in the age of subjects, gestational age, birthweight, serum unconjugated bilirubin concentration,

serum albumin concentration, and study design. The

onset of phototherapy was also an influencing factor.

Although there were no statistically significantdifferences in age and gender between subjects who

had neurological impairment and who had no neu-

rological impairment (Table 3), the clinical features

were different. Currently the association betweengender and neurological impairment is still unclear.

There is an association between birth weight and

bilirubin encephalopathy.5,7,8This is associated withnegative correlation between birth weight and perme-

ability of BBB.6In multivariate analysis (Table 4), therewas no association in both. This was because Dubowitz

score determined gestational age subjectively.

Phototherapy is the most common mean of treat-ment of hyperbilirubinemia.33 Phototherapy, by

photoisomerization and photo oxidation, results in the

formation of more polar, water-soluble bilirubin prod-

ucts.19,28,33The most important reaction appears tobe the formation of lamirubin, a stable structural photo

isomer. Lamirubin does not require conjugation,33and

is rapidly excreted in bile and urine.15,19,34In our study,

neurological impairment was found although the sub-jects had received phototherapy. This finding indi-

cated that the brain had been exposed to

unconjugated bilirubin for 2 hours or more at the ini-

tiation of phototherapy.35This problem may be causedby some factors such as late initiation of photo therapy

attributable to limitation of photo therapy facilities,

poor light quality due to the use of the light more than

2000 hours, and delay to establish diagnosis of hyper-bilirubinemia.

Though we found that there was a relationship

between hyperbilirubinemia and neurological impair-

ment, a prospective cohort study needs to be done be-cause there might be recall bias in a retrospective study.

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